Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.
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Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome (AS), thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane (GBM) findings. Secondary FSGS is known to develop in classic AS at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical finding at diagnosis was proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic-range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin GBM, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.
Collagen Type IV
DNA Mutational Analysis
Glomerular Basement Membrane
Glomerulosclerosis, Focal Segmental
Published Version (Please cite this version)10.1038/ki.2014.305
Publication InfoMalone, Andrew F; Phelan, Paul J; Hall, Gentzon; Cetincelik, Umran; Homstad, Alison; Alonso, Andrea S; ... Gbadegesin, Rasheed A (2014). Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int, 86(6). pp. 1253-1259. 10.1038/ki.2014.305. Retrieved from https://hdl.handle.net/10161/11616.
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Professor of Pediatrics
Molecular genetics of glomerular disease Genetic risk factors for childhood onset idiopathic nephrotic syndrome
Professor of Pathology
A major focus of both my clinical practice and investigative work is the diagnosis and treatment of disorders affecting solid-organ transplant recipients, particularly infectious complications. For the past 15 years, I have served as the primary pathologist for one of the largest lung transplant programs in the world; in the process contributing to over 20 peer-reviewed publications on complications of lung transplantation, including infections, gastroesophageal reflux, tumors, and antibod
Professor of Medicine
Ongoing work focuses on problems of immediate clinical relevance in renal and pancreas transplantation, including issues related to immunosuppression, infection, and cardiovascular events as well as hypertension. Research methodologies employed include randomized clinical trials, cohort studies, and retrospective multivariable analyses based on the transplant database.
Assistant Professor of Medicine
I serve as the Associate Program Director for the Nephrology Fellowship Program. My goal is to work with each fellow to ensure they develop a successful career in whatever direction they choose. In my role as Director of Medical Student Research in the Department of Medicine I help promote research in the Department of Medicine during the 3rd year of medical school at Duke University.Nephrology Fellowship Progra
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